Delayed Spatial Alternation Task Research Articles

Coordinated Interactions between the Hippocampus and Retrosplenial Cortex in Spatial Memory.

While a hippocampal-cortical dialogue is generally thought to mediate memory consolidation, which is crucial for engram function, how it works remains largely unknown. Here, we examined the interplay of neural signals from the retrosplenial cortex (RSC), a neocortical region, and from the hippocampus in memory consolidation by simultaneously recording sharp-wave ripples (SWRs) of dorsal hippocampal CA1 and neural signals of RSC in free-moving mice during the delayed spatial alternation task (DSAT) and subsequent sleep. Hippocampal-RSC coordination during SWRs was identified in nonrapid eye movement (NREM) sleep, reflecting neural reactivation of decision-making in the task, as shown by a peak reactivation strength within SWRs. Using modified generalized linear models (GLMs), we traced information flow through the RSC-CA1-RSC circuit around SWRs during sleep following DSAT. Our findings show that after spatial training, RSC excitatory neurons typically increase CA1 activity prior to hippocampal SWRs, potentially initiating hippocampal memory replay, while inhibitory neurons are activated by hippocampal outputs in post-SWRs. We further identified certain excitatory neurons in the RSC that encoded spatial information related to the DSAT. These neurons, classified as splitters and location-related cells, showed varied responses to hippocampal SWRs. Overall, our study highlights the complex dynamics between the RSC and hippocampal CA1 region during SWRs in NREM sleep, underscoring their critical interplay in spatial memory consolidation.

Using the delayed spatial alternation task to assess environmentally associated changes in working memory in very young children

BackgroundWorking memory (WM) is critical for problem solving and reasoning. Beginning in infancy, children show WM capacity increasing with age but there are few validated tests of WM in very young children. Because rapid brain development may increase susceptibility to adverse impacts of prenatal neurotoxicant exposure, such as lead, tests of WM in very young children would help to delineate onset of developmental problems and windows of susceptibility. PurposeOur objective was to assess the feasibility of administering a Delayed Spatial Alternation Task (DSAT) to measure WM among 18- and 24-month old children enrolled in an ongoing longitudinal birth cohort study and compare DSAT performance with age and general cognitive development. We further explored whether prenatal lead exposure impacted DSAT performance. MethodsWe assessed 457 mother-child pairs participating in the Programming Research in Obesity, GRowth, Environment and Social Stressors (PROGRESS) Study in Mexico City. The DSAT and Bayley Scales of Infant Development (BSID-III) were administered at 18- and 24-months. Lead was measured in maternal blood collected during pregnancy (MBPb) and in a subsample of children at 24-months (CBPb). We regressed DSAT measures on MBPb and CBPb, child sex, and maternal age, education, socioeconomic status, and household smoking. We compared DSAT performance to BSID-III performance with adjusted residuals. Results24-month children perform better on the DSAT than 18-month children; 24-month subjects reached a higher level on the DSAT (3.3 (0.86) vs. 2.4 (0.97), p < 0.01), and had a higher number of correct responses (20.3 vs. 17.2, p < 0.01). In all DSAT parameters, females performed better than males. Maternal education predicted better DSAT performance; household smoking predicted worse DSAT performance. A higher number of correct responses was associated with higher BSID-III Cognitive scales at 18 months (r = 0.20, p < 0.01) and 24 months (r = 0.27, p < 0.01). MBPb and CPBb did not significantly predict DSAT performance. ConclusionImproved performance on the DSAT with increasing age, the positive correlation with the BSID-III cognitive and language scales and the correlation with common sociodemographic predictors of neurodevelopment demonstrate the validity of the DSAT as a test of infant development.

The effects of the botanical estrogen, isoliquiritigenin on delayed spatial alternation

Age-related declines in cognitive function can impair working memory, reduce speed of processing, and alter attentional resources. In particular, menopausal women may show an acceleration in the rate of cognitive decline as well as an increased vulnerability to brain diseases as estrogens may play a neuroprotective and neurotrophic role in the brain. To treat menopausal symptoms, many women turn to botanical estrogens that are promoted as a safe and natural alternative to traditional hormone replacement therapy. However, the majority of these compounds have not been systematically evaluated for efficacy and safety. The current study investigated the efficacy of the commercially available botanical estrogenic compound isoliquiritigenin (ISL) to alter performance on an operant working memory task, delayed spatial alternation (DSA). ISL is a compound found in licorice root that has been shown to have a wide range of effects on different biological systems, including estrogenic properties. This botanical is currently being used in over the counter dietary supplements. Middle-aged (12-month old) Long-Evans female rats were ovariectomized and orally dosed with either 0 mg, 6 mg, 12 mg or 24 mg of ISL 60 min before testing on the DSA task. The DSA task required the rat to alternate its responses between two retractable levers in order to earn food rewards. Random delays of 0, 3, 6, 9 or 18 s were imposed between opportunities to press. ISL treatment failed to alter DSA performance. Previous work from our research group has found that estrogenic compounds, including 17β-estradiol and the botanical estrogen genistein impair performance on the DSA task. The goal of our botanical estrogens research is to find compounds that offer some of the beneficial effects of estrogen supplementation, without the harmful effects. This work suggests that ISL may not carry the cognitive risks associated with most other estrogenic compounds tested to date.

Effects of treadmill exercise intensity on spatial working memory and long-term memory in rats

AimsModerate exercise promotes learning and memory. Most studies mainly focused on memory exercise effects of in the ageing and patients. There is lack of quantitative research about effect of regular exercise intensity on different memory types in normal subjects. Present study investigated the effects of different intensities of treadmill exercise on working memory and long-term memory. Main methodsFifty female Wistar rats were trained by T-maze delayed spatial alternation (DSA) task with 3 delays (10s, 60s and 300s). Then they got a 30min treadmill exercise for 30days in 4 intensities (control, 0m/min; lower, 15m/min; middle, 20m/min, and higher, 30m/min). Then animals were tested in DSA, passive avoidance and Morris water maze tasks. Key findings1. Exercise increased the neuronal density of hippocampal subregions (CA1, CA3 and dentate gyrus) vs. naïve/control. 2. In DSA task, all groups have similar baseline, lower intensity improved 10s delay accuracy vs. baseline/control; middle and higher intensities improved 300s delay accuracy vs. baseline/control. 3. In water maze learning, all groups successfully found the platform, but middle intensity improved platform field crossing times vs. control in test phase. SignificancePresent results suggested that treadmill exercise can improve long-term spatial memory and working memory; lower intensity benefits to short-term delayed working memory, and middle or higher intensity benefits to long-term delayed working memory. There was an inverted U dose-effect relationship between exercise intensity and memory performance, but exercise -working memory effect was impacted by delay duration.

Theta phase shift in spike timing and modulation of gamma oscillation: a dynamic code for spatial alternation during fixation in rat hippocampal area CA1

Although hippocampus is thought to perform various memory-related functions, little is known about the underlying dynamics of neural activity during a preparatory stage before a spatial choice. Here we focus on neural activity that reflects a memory-based code for spatial alternation, independent of current sensory and motor parameters. We recorded multiple single units and local field potentials in the stratum pyramidale of dorsal hippocampal area CA1 while rats performed a delayed spatial-alternation task. This task includes a 1-s fixation in a nose-poke port between selecting alternating reward sites and so provides time-locked enter-and-leave events. At the single-unit level, we concentrated on neurons that were specifically active during the 1-s fixation period, when the rat was ready and waiting for a cue to pursue the task. These neurons showed selective activity as a function of the alternation sequence. We observed a marked shift in the phase timing of the neuronal spikes relative to the theta oscillation, from the theta peak at the beginning of fixation to the theta trough at the end of fixation. The gamma-band local field potential also changed during the fixation period: the high-gamma power (60-90 Hz) decreased and the low-gamma power (30-45 Hz) increased toward the end. These two gamma components were observed at different phases of the ongoing theta oscillation. Taken together, our data suggest a switch in the type of information processing through the fixation period, from externally cued to internally generated.

The effects of dietary treatment with S-equol on learning and memory processes in middle-aged ovariectomized rats

The use of over-the-counter botanical estrogens containing isolated soy isoflavones, including genistein and daidzein, has become a popular alternative to traditional hormone therapies. Menopausal women use these products as an aide in healthy aging, including for the maintenance of cognitive function. The safety and efficacy of many of these commercial preparations remain unknown. Previous research in our lab found that treatment of ovariectomized (OVX) female Long-Evans rats with genistein impaired working memory in an operant delayed spatial alternation (DSA) task and response learning in a plus-maze, but enhanced place learning assessed in the plus-maze. The present study further examined the effects of isolated isoflavones on working memory and place learning by treating middle-aged (12–13month old) OVX female Long-Evans rats with S-equol, the exclusive enantiomer produced by metabolism of daidzein in the mammalian gut. S-equol binds selectively to ERβ with an affinity similar to that of genistein but has low transcriptional potency. For DSA testing, S-equol at 1.94, 0.97mg, or 0mg (sucrose control) was orally administered to animals daily, 30min before behavioral testing, and again both 4 and 8hours after the first treatment. Rats were tested on the DSA task following the first, morning dose. For place learning, rats received 0.97mgS-equol every 4hours during the light portion of the cycle beginning 48hours prior to behavioral testing (total exposure 8.7mgS-equol). S-equol treatment was largely without effect on the DSA and place learning tasks. This is the first study to test the behavioral effects of isolated S-equol in OVX rodents, and shows that, unlike genistein or estradiol, repeated daily treatment with this isoflavone metabolite does not alter learning and memory processes in middle-aged OVX rats.

Voluntary exercise impairs initial delayed spatial alternation performance in estradiol treated ovariectomized middle-aged rats

Estrogens differentially modulate behavior in the adult female rodent. Voluntary exercise can also impact behavior, often reversing age associated decrements in memory processes. Our research group has published a series of papers reporting a deficit in the acquisition of an operant working memory task, delayed spatial alternation (DSA), following 17β-estradiol treatment to middle-aged ovariectomized (OVX) rats. The current study examined if voluntary exercise could attenuate the 17β-estradiol induced deficits on DSA performance. OVX 12-month old Long–Evans rats were implanted with a Silastic capsule containing 17β-estradiol (10% in cholesterol: low physiological range) or with a blank capsule. A subset of the 17β-estradiol and OVX untreated rats were given free access to a running wheel in their home cage. All rats were tested for 40 sessions on the DSA task. Surprisingly, we found running wheel access to impair initial acquisition of the DSA task in 17β-estradiol treated rats, an effect not seen in OVX untreated rats given running wheel access. This deficit was driven by an increase in perseverative responding on a lever no longer associated with reinforcement. We also report for the first time a 17β-estradiol induced impairment on the DSA task following a long intertrial delay (18-sec), an effect revealed following more extended testing than in our previous studies (15 additional sessions). Overall, running wheel access increased initial error rate on the DSA task in 17β-estradiol treated middle-aged OVX rats, and failed to prevent the 17β-estradiol induced deficits in performance of the operant DSA task in later testing sessions.

Working memory in bisphenol-A treated middle-aged ovariectomized rats

Over 90% of the U.S. population has detectable bisphenol-A (BPA) in their urine according to recent biomonitoring data. BPA is best known for its estrogenic properties, and most rodent research on the nervous system effects of BPA has focused on determining if chronic exposures during pre- and perinatal development have organizational effects on brain development and behavior. Estrogens also have important impacts on brain and behavior during adulthood, particularly in females during aging, but the impact of BPA on the adult brain is less studied. We have published a series of studies documenting that chronic exposure to various estrogens including 17β-estradiol, ERβ selective SERMs and soy phytoestrogens impairs performance of middle-aged female rats on an operant working memory task. The purpose of this study was to determine if chronic oral exposure to BPA would alter working memory on this same task. Ovariectomized (OVX) middle-aged Long Evans rats were tested on an operant delayed spatial alternation (DSA) task. Rats were treated for 8–10weeks with either a 0 (vehicle control), 5 or 50μg/kgbw/day oral bolus of BPA. A subset of the vehicle control rats was implanted with a Silastic implant containing 17β-estradiol (low physiological range) to serve as a positive control. All rats were tested for 25 sessions on the DSA task. BPA treatment did not influence performance accuracy on the DSA task, whereas 17β-estradiol significantly impaired performance, as previously reported. The results of this study suggest that chronic oral exposure to BPA does not alter working memory processes of middle-aged OVX rats assessed by this operant DSA task.

Effects of multiple daily genistein treatments on delayed alternation and a differential reinforcement of low rates of responding task in middle-aged rats

The use of extracts that are highly enriched in phytoestrogens, such as genistein, has become popular to promote various aspects of healthy aging, including maintenance of cognitive function. These compounds are promoted to menopausal women as safe, natural alternatives to traditional estrogen therapies, yet their safety and efficacy are poorly understood. Previous research in our lab found that once daily oral treatment of ovariectomized female Long–Evans (LE) rats with the soy phytoestrogen, genistein resulted in subtle deficits in performance on cognitive tasks assessing working memory and response inhibition/timing ability. The present study further modeled exposure of the menopausal woman to genistein by treating 14-month old ovariectomized female LE rats three times daily at a dose of genistein resulting in serum concentrations similar to those that could be achieved in humans consuming either a commercially available soy isoflavone supplement or a diet high in these phytoestrogens. Genistein (3.4mg/kg) or sucrose control pellets were orally administered to animals daily, 30min before behavioral testing, and again both 4 and 8h after the first treatment. The test battery consisted of a delayed spatial alternation task (DSA) that tested working memory and a differential reinforcement of low rates of responding (DRL) task that tested inhibitory control/timing. Genistein treatment impaired DSA performance relative to sucrose controls. Performance on the DRL task was largely unaffected by genistein treatment. Although the impairment measured on DSA was less pronounced than that we have previously reported following chronic treatment with 17β-estradiol, the pattern of the deficit was very similar to that observed with 17β-estradiol.

Impact of estrogen receptor alpha and beta agonists on delayed alternation in middle-aged rats

Estrogens act in the adult brain to modulate cognition, enhancing performance on some learning tests and impairing performance on others. Our previous research has revealed an impairing effect of chronic 17β-estradiol treatment in young and aged rats on a prefrontally-mediated working memory task, delayed spatial alternation (DSA). Little is known about the mechanisms of these impairing effects. The current study examined the effects of selective estrogen receptor (ER) α or ERβ activation on DSA performance in middle-aged female rats. Ovariectomized 12 month old Long–Evans (LE) rats were treated by subcutaneous injection with the ERα agonist propyl pyrazole triol (PPT) or the ERβ agonist diarylpropionitrile (DPN) at 0.02, 0.08, or 0.20 mg/kg/day, or with oil vehicle and tested on an operant variable delay DSA task. A 17β-estradiol group (10% in cholesterol) was included as a positive control group. We replicated our previous finding of a 17β-estradiol induced deficit on DSA performance and this effect was paralleled by low dose (0.02 mg/kg/day) DPN treatment. Higher doses of DPN failed to produce a significant change in performance. The highest dose of PPT (0.20 mg/kg/day) also impaired performance, but this effect was subtle and limited to the longest delay during the final block of testing. These data confirm our earlier findings that chronic 17β-estradiol treatment has an impairing effect on the DSA task, and suggest that ERβ activation may underlie the deficit.

Impact of dietary genistein and aging on executive function in rats

Genistein is an estrogenic soy isoflavone widely promoted for healthy aging, but its effects on cognitive function are not well-understood. We examined the cognitive effects of once daily oral genistein treatment at two doses (approximately 162μg/kg/day low dose and a 323μg/kg/day high dose) in ovariectomized young (7month), middle-aged (16month), and old (22month) Long–Evans rats. Operant tasks including delayed spatial alternation (DSA), differential reinforcement of low rates of responding (DRL), and reversal learning that tap prefrontal cortical function were used to assess working memory, inhibitory control/timing, and strategy shifting, respectively. At the conclusion of cognitive testing, brains were collected and relative densities of D1 and D2 dopamine receptors and dopamine transporter (DAT) were measured in the prefrontal cortex. On the DSA task, the high dose old group performed worse than both the high dose young and middle-aged groups. On the DRL task, the high dose of genistein resulted in a marginally significant impairment in the ratio of reinforced to non-reinforced lever presses. This effect was present across age groups. Age effects were also found as old rats performed more poorly than the young and middle-aged rats on the DSA overall. In contrast, middle-aged and old rats made fewer lever presses on the DRL than did the young rats, a pattern of behavior associated with better performance on this task. Moreover, while DAT levels overall decreased with age, genistein treatment produced an increase in DAT expression in old rats relative to similarly aged control rats. D1 and D2 densities did not differ between genistein dose groups or by age. These results highlight the fact that aspects of executive function are differentially sensitive to both genistein exposure and aging and suggest that altered prefrontal dopamine function could potentially play a role in mediating these effects.

Chronic estradiol replacement impairs performance on an operant delayed spatial alternation task in young, middle-aged, and old rats

The current study examined effects of chronic estradiol replacement on a prefrontally-mediated working memory task at different ages in a rodent model. Ovariectomized young, middle-aged, and old Long–Evans rats were given 5% or 10% 17β-estradiol in cholesterol vehicle via Silastic implants and tested on an operant delayed spatial alternation task (DSA). The two estradiol exposed groups did not perform as well as the vehicle control group did. Deficits were present at all but the longest delay, where all groups including the vehicle control group performed poorly. Surprisingly, there was not a significant effect of age or an age by estradiol interaction, despite the fact that old rats had longer latencies to respond after both correct and incorrect lever presses. These data confirm our earlier finding that chronic estradiol treatment has an impairing effect on working memory as measured on DSA task. However, contrary to expectations, young, middle-aged and old rats were similarly impaired by chronic estradiol treatment; there were no indications of differential effects at different periods of the lifespan. Also contrary to expectations, there were no indications of a decline in DSA performance with advancing age. Overall, the results demonstrate that chronic estradiol exposure causes deficits in the DSA performance of ovariectomized female rats, not only in young adulthood, but also at older ages analogous to those at which hormone replacement therapy is commonly prescribed in humans.

Effects of chronic estradiol treatment on delayed spatial alternation and differential reinforcement of low rates of responding.

Estrogens have been shown to both enhance and impair cognitive function depending on several factors, including regimen of hormone treatment, age of subject, and task attributes. In rodent models, estradiol tends to enhance spatial learning and impair response or cued learning, but effects on executive functions are less well-studied. In this experiment, spatial working memory and response inhibition were tested using delayed spatial alternation (DSA) and differential reinforcement of low rates of responding (DRL) tasks in ovariectomized rats that were given chronic estradiol via Silastic implants resulting in serum estradiol concentrations of 86.2 +/- 8.2 (SEM) pg/ml. Rats were tested for 25 days DSA with variable delays of 0, 3, 6, 9, and 18 seconds between lever presentations, followed by 30 days on a DRL-15s operant schedule. Estradiol-replaced rats showed a significantly lower proportion of correct responses on the DSA task compared to vehicle-implanted ovariectomized animals. On DRL, estradiol-treated rats showed a lower ratio of reinforced to nonreinforced presses. These data suggest that chronic estrogen exposure may impair rats' abilities on measures of executive function including working memory and response inhibition.

Effects of Gestational and Lactational Exposure to TCDD or Coplanar PCBs on Spatial Learning

Recently we reported that in utero and lactational exposure to specific ortho-substituted polychlorinated biphenyl (PCB) congeners resulted in a learning deficit on a delayed spatial alternation (DSA) task in female rats. In this study, spatial learning and memory was assessed following in utero and lactational exposure to coplanar PCBs or 2,3,7,8-tetrachlorodibenzo- p -dioxin (TCDD). Time-mated Sprague-Dawley rats were dosed with PCB 77 (3,3′,4,4′-tetrachlorobiphenyl), 2 or 8 mg/kg/day; PCB 126 (3,3′,4,4′,5-pentachlorobiphenyl), 0.25 or 1.0 μg/kg/day; TCDD, 0.025 or 0.1 μg/kg/day; or corn oil vehicle via gavage on gestation days 10–16. Litters were culled to eight on day 2 and weaned on day 21. Beginning on day 80, one male and one female from each litter were tested on an eight-arm radial maze working memory task. The TCDD-exposed rats displayed pronounced decreases in errors relative to controls. PCB 77- and PCB 126-exposed rats showed similar, but less pronounced, decreases in errors. The same animals were later tested on a T-maze DSA task, but no differences among groups were observed. In conclusion, perinatal exposure to low doses of TCDD or structurally related coplanar PCBs appeared to facilitate acquisition of a working memory task on the radial arm maze. This effect was very different from that previously observed in rats exposed to ortho-substituted PCB congeners. The rats exposed to ortho-substituted PCBs did not differ from controls on the radial arm maze and were impaired on the T-maze DSA task. Together these findings suggest that coplanar and ortho-substituted PCBs may have different mechanisms of action on the CNS.

Effects of gestational and lactational exposure to TCDD or coplanar PCBs on spatial learning

Recently we reported that in utero and lactational exposure to specific ortho-substituted polychlorinated biphenyl (PCB) congeners resulted in a learning deficit on a delayed spatial alternation (DSA) task in female rats. In this study, spatial learning and memory was assessed following in utero and lactational exposure to coplanar PCBs or 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD). Time-mated Sprague-Dawley rats were dosed with PCB 77 (3,3′,4,4′-tetrachlorobiphenyl), 2 or 8 mg/kg/day; PCB 126 (3,3′,4,4′,5-pentachlorobiphenyl), 0.25 or 1.0 μg/kg/day; TCDD, 0.025 or 0.1 μg/kg/day; or corn oil vehicle via gavage on gestation days 10–16. Litters were culled to eight on day 2 and weaned on day 21. Beginning on day 80, one male and one female from each litter were tested on an eight-arm radial maze working memory task. The TCDD-exposed rats displayed pronounced decreases in errors relative to controls. PCB 77- and PCB 126-exposed rats showed similar, but less pronounced, decreases in errors. The same animals were later tested on a T-maze DSA task, but no differences among groups were observed. In conclusion, perinatal exposure to low doses of TCDD or structurally related coplanar PCBs appeared to facilitate acquisition of a working memory task on the radial arm maze. This effect was very different from that previously observed in rats exposed to ortho-substituted PCB congeners. The rats exposed to ortho-substituted PCBs did not differ from controls on the radial arm maze and were impaired on the T-maze DSA task. Together these findings suggest that coplanar and ortho-substituted PCBs may have different mechanisms of action on the CNS.

Ginkgo biloba extract facilitates recovery from penetrating brain injury in adult male rats

Adult, male Sprague-Dawley rats received 100 mg/kg Ginkgo biloba extract (GBE) intraperitoneally for 30 days. GBE reduced overall activity and decreased sensitivity to light in the open field maze. The rats were also less responsive to noxious stimuli after 13 days of treatment with GBE. After the last injection, all subjects were trained on a delayed-spatial alternation task. Subsequent to acquisition of the spatial task, the rats received either sham operations and saline or bilateral frontal cortex lesions treated with either saline or GBE. Thirty additional days of treatment began on the day of injury, and open field behavior, analgesia, and metabolic activity measurements were again measured. The rats with lesions treated with saline were more active than their GBE-treated counterparts and sham controls but there were no differences in response to illumination or noxious stimuli. Retention of the delayed-spatial alternation indicated that rats with lesions treated with GBE were less impaired than brain-injured subjects receiving saline treatment. Histological examination showed that GBE reduced the extent of brain swelling in response to the injury.

Hormonal state affects recovery from frontal cortex lesions in adult female rats

Pseudopregnant and normal cycling female Sprague-Dawley rats were trained on a delayed-spatial alternation task. After acquisition training, the subjects received frontal cortex lesions and were subsequently tested for retention. The pseudopregnant animals with lesions were less impaired than their normal cycling counterparts. Learning and retention testing were not affected by hormonal status in the noninjured controls. Histological examination showed that the normal cycling rats with frontal cortex lesions possessed enlarged ventricles, indicating the presence of edema in this surgical group. However, brain tissue of pseudopregnant subjects given the same lesion and sham operates of both hormonal states did not display this characteristic of edema. We speculate that the behavioral and anatomical impairment observed in the normal cycling females with brain injury is due to higher levels of vasopressin, a potent vasoconstrictor synchronized with brain injury in our manipulation.